ABSTRACT
The C-transmembrane form of prion protein (CtmPrP) has been implicated in prion disease pathogenesis, but the factors underlying its biogenesis and cyotoxic potential remain unclear. Here we show that CtmPrP interferes with cytokinesis in cell lines where it is transported to the plasma membrane. These cells fail to separate following cell division, assume a variety of shapes and sizes, and contain multiple nuclei, some of which are pyknotic. Furthermore, the synthesis and transport of CtmPrP to the plasma membrane are modulated through a complex interaction between cis- and trans-acting factors and the endoplasmic reticulum translocation machinery. Thus, insertion of eight amino acids before or within the N region of the N signal peptide (N-SP) of PrP results in the exclusive synthesis of CtmPrP regardless of the charge conferred to the N region. Subsequent processing and transport of CtmPrP are modulated by specific amino acids in the N region of the N-SP and by the cell line of expression. Although the trigger for CtmPrP upregulation in naturally occurring prion disorders remains elusive, these data highlight the underlying mechanisms of CtmPrP biogenesis and neurotoxicity and reinforce the idea that CtmPrP may serve as the proximate cause of neuronal death in certain prion disorders.